Future Direction in Pharmacotherapy for Non-Neurogenic Male Lower Urinary Tract Symptoms

8/13/2019 Future Direction in Pharmacotherapy for Non-Neurogenic Male Lower Urinary Tract Symptoms

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Platinum Priority Review Voiding DysfunctionEditorial by Jean-Nicolas Cornu on pp. 622623 of this issue

Future Direction in Pharmacotherapy for Non-neurogenic Male

Lower Urinary Tract Symptoms

Roberto Solera, Karl-Erik Andersson b, Michael B. Chancellorc, Christopher R. Chapple d,

William C. de Groate, Marcus J. Drake f, Christian Gratzke g, Richard Lee h, Francisco Cruzi,*

a

Division of Urology, Federal University of Sao Paulo and Hospital Israelita Albert Einstein, Sao Paulo, Brazil; b

Institute of Regenerative Medicine, WakeForest University School of Medicine and Department of Urology, Wake Forest Baptist Medical Center, Winston Salem, NC, USA; c Oakland University William

Beaumont School of Medicine, Royal Oak, MI, USA; d Department of Urology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust,

Sheffield, UK; e Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA; fBristol Urological Institute

and School of Clinical Sciences, University of Bristol, Bristol, UK; g Department of Urology, LMU Munich, Campus Grosshadern, Munich, Germany; hJames

Buchanan Brady Foundation, Department of Urology, Weill Cornell Medical College, New York, NY, USA; i Department of Urology, Hospital de S. Joao,

University of Porto, Porto, Portugal

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j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m

Article info

Article history:

Accepted April 29, 2013

Published online ahead of

print on May 7, 2013

Keywords:

Benign prostatic hyperplasia

Bladder

Lower urinary tract symptoms

Male

Pathophysiology

Pharmacotherapy

Prostate

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Abstract

Background: The pathophysiology of male lower urinary tract symptoms (LUTS) ishighly complex and multifactorial. The shift in perception that LUTS are not sex or organspecific has not been followed by significant innovations regarding the available drugclasses.

Objective: To review pathophysiologic mechanisms and clinical and experimental datarelated to the development of new pharmacologic treatments for male LUTS.Evidence acquisition: The PubMed database was used to identify articles describingexperimental and clinical studies of pathophysiologic mechanisms contributing to maleLUTS and, supported by them, new pharmacotherapies with clinical or experimentalevidence in the field.Evidence synthesis: Several pathologic processes (eg, androgen signaling, inflammation,and metabolic factors) and targets (eg, the urothelium, prostate, interstitial cells,detrusor, neurotransmitters, neuromodulators, and receptors) have been implicatedin male LUTS. Some newly introduced drugs,such as phosphodiesterase type 5 inhibitorsand b3-adrenergic agonists, have just started broad use in clinical practice. Drugs withpotential benefit, such as vitamin D3 receptor analogs, gonadotropin-releasing hormoneantagonists, cannabinoids, and drugs injected into the prostate, have been evaluated inexperimental studies and have progressed to clinical trials. However, safety and efficacydata forthese drugs are still scarce. Some compounds with interesting profiles have onlybeen tested in experimental settings (eg, transient receptor potential channel blockers,Rho-kinase inhibitors, purinergic receptor blockers, and endothelin-converting enzymeinhibitors).Conclusions: Newpathophysiologic mechanisms of male LUTS aredescribed that lead tothe continuous development of new pharmacotherapies. To date, few drugs have beenadded to the current armamentarium, and several are in various phases of clinical orexperimental investigation.

# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Hospital de S. Joao, University of Porto, Porto,

Portugal, Alameda Prof. Hernani, 4200-319, Porto, Portugal. Tel. +35 1 91 3231123;

Fax: +35 1 22 5513655.

E-mail address:[email protected](F. Cruz).

0302-2838/$ see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.eururo.2013.04.042
http://dx.doi.org/10.1016/j.eururo.2013.04.042http://www.eu-acme.org/europeanurologyhttp://www.eu-acme.org/europeanurologymailto:[email protected]://dx.doi.org/10.1016/j.eururo.2013.04.042http://dx.doi.org/10.1016/j.eururo.2013.04.042mailto:[email protected]://www.eu-acme.org/europeanurologyhttp://www.eu-acme.org/europeanurologyhttp://dx.doi.org/10.1016/j.eururo.2013.04.042


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1. Introduction

Lower urinary tract symptoms (LUTS) can be subdivided

into storage (overactive bladder [OAB]), voiding, and

postmicturition subtypes, with OAB symptoms generally

the most bothersome [1]. LUTS in men are not disease

specific. Benign prostatic hyperplasia (BPH) as a histologic

diagnosis and clinical BPH are terms best avoided whendescribing LUTS in men, due to a bias toward a potential role

of the prostate versus other likely contributory mecha-

nisms. A variety of experimental, epidemiologic, and clinical

data have shown that LUTS, particularly the storage

component (OAB), are multifactorial in origin[2,3].

BPHis extremely prevalent in the aging male population,

increasing from 42% in men 5059 yr of age to 88% in men

>80 yr[4]. Approximately 50% of men with histologic BPH

develop benign prostatic enlargement (BPE), but only

2550% of men with histologic BPH have LUTS [2,5,6].

Clearly the inverse is also true: The presence of LUTS in men

does not conclusively signify a diagnosis of benign prostatic

obstruction (BPO) or bladder outlet obstruction (BOO). Inseries of male patients presenting with LUTS, only 50% were

found to have urodynamically proven BOO [79]. LUTS

suggestive of BOO may actually be due to an underactive

detrusor, regardless of whether BOO is present [10]. Overall,

the direct correlation of BPH, BPE, BOO, and LUTS is poor.

The storage symptom complex (OAB) is defined as

urgency, with or without urge incontinence, usually with

frequency and nocturia[1]. This symptom syndrome was

previously considered to be a female disorder [11].

However, using the 2002 International Incontinence Society

definitions, the Extended Prostate Cancer Index Composite

study evaluated LUTS in 19 165 individuals 18 yr of age in

five countries and reported a similar prevalence of OAB in

men and women10.8% and 12.8%, respectively[12].

To date, the first-line medical therapy for men with LUTS

is a1-adrenergic receptor antagonists (a-blockers) and 5a-

reductase inhibitors (5-ARIs) [5,13]. Despite the high

prevalence of OAB symptoms in men, antimuscarinics are

not commonly used. Clinical trials have been conducted to

assess the efficacy of combination therapy with existing

drugs:a-blocker plus 5-ARI,a-blocker plus antimuscarinics,

and 5-ARI plus antimuscarinics [1416]. In addition, new

information on different pathophysiologic processes related

to LUTS has been reported [3,17]. The present paper

considers pathophysiologic mechanisms and possible

targets for drug therapy, and it reviews the clinical and

experimental data related to the development of these new

treatments for male LUTS.

2. Evidence acquisition

A literature search wasperformed via the PubMed database.

Articles describing experimental or clinical data on

pathophysiologic mechanisms of male LUTS were selected.

Based on the targets and mechanisms included in the first

section, articles about new pharmacotherapies for male

LUTS were chosen. For this section, newly introduced drugs,

drugs in the phase of clinical trials, and drugs in the phase of

experimental investigation were included. Only studies

published in English were included. Nocturia was not

included in the search. A recent review covered this topic

comprehensively[18].

3. Evidence synthesis

3.1. Pathophysiologic mechanisms and targets for future

therapies (Fig. 1)

3.1.1. Androgen and estrogen receptor signaling in prostatic tissue

remodeling

Androgens play a key role in the growthand development of

the prostate as well as in the pathogenesis of BPH. Subjects

castrated before puberty do not develop BPH [19].

Testosterone is converted to dihydrotestosterone (DHT)

by 5a-reductases (5-ARs) predominantly in the stromal

tissue. DHT is more potent than testosterone and also has a

higher affinity for the androgen receptor (AR), allowing it to

accumulate in the prostate even when circulating testos-

terone levels are low. Intracellular ARs are activated by

androgen binding and/or through interactions with growth

factor (GF) signaling and protein kinase A pathways[20].

Androgen deprivation, either surgically or chemically with

finasteride, a 5-AR type1 inhibitor, or dutasteride, a 5-AR

type1 and 2 inhibitor, reduce both circulating and

intraprostatic DHT, and prostate volume by 20% [21,22].

Conversely, a few recent studies have pointed out the

effect of low androgen levels on urinary functions. Late-

onset hypogonadism has been associated not only with

erectile dysfunction but also with LUTS. A definitive

pathophysiologic explanation is not clear, but the basis

for this association relies on the distribution of ARsthroughout the LUTS, the impact of androgens on the

autonomic nervous system, nitric oxide synthase, phos-

phodiesterase type 5 (PDE5), RhoA/Rho kinase (ROK)

activity, and pelvic blood flow [23]. In a cohort of

community-dwelling older men, the ones with higher

midlife levels of testosterone to DHT and bioavailable

testosterone had a decreased 20-yr risk of LUTS[24]. Male

hypogonadism has recently been associated with metabolic

syndrome, probably via increased aromatase activity,

hypogonadotropic hypogonadism, and increased activity

of the hypothalamicpituitaryadrenal axis[25].

Estrogen and estrogen-mimicking compounds may also

have a role in prostate biology because estrogen receptor(ER)-a is associated with proliferation and ER-b is

associated with regulation of proliferation and induction

of apoptosis[26]. In the aging man, there is a progressive

decrease in the ratio of circulating levels of androgens to

estrogens. This is believed to contribute to BPH develop-

ment through a mitogenic effect on ER-a. Aromatase, which

converts androgen precursors to aromatic estrogens, has

been identified in the prostatic stroma[21].

3.1.2. Urothelium

The urothelium represents more than a barrier in the

bladder. Urothelial cells express nociceptors and mechan-

oreceptors and when stimulated release several substances

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such as adenosine triphosphate (ATP), nitric oxide (NO),

acetylcholine (ACh), cytokines, prostanoids, and nerve

growth factor (NGF), among others. During the storage

phase in patients with detrusor overactivity (DO), possible

release of ACh from the urothelium may initiate spontane-

ous localized contractile activity of the detrusor and trigger

afferent noise[27].

ATP acts on purinergic receptors: P2X (ligand-gated

cation channel) and P2Y (G protein-coupled). Several

purinergic receptors are expressed in the urothelium: All

seven P2X receptors subunits (17) and P2Y subunits 1, 2,

and 4. P2X3 receptors were detected on pelvic afferent

nerves, dorsal root ganglia, bladder wall, and in a

suburothelial plexus of afferent nerves[2831].

3.1.3. Interstitial cells

Interstitial cells (ICs) occur in the lamina propria and within

and adjacent to smooth muscle bundles. ICs in the lamina

propria respond to ATP by firing Ca2+ transients, suggesting

the existence of a sensory transduction signaling system. In

the detrusor, ICs respond to cholinergic agonists, preferen-

tially mediated by M3 receptors [32]. ICs may directly

generate detrusor contractile activity during filling and be

involved in ACh-mediated voiding contractions [32,33]. I n a

rat model of partial BOO, there was an increase of ICs in the

suburothelial and muscle layers expressing endothelial

nitric oxide synthase and neuronal nitric oxide synthase

[34]. Imatinib mesylate, a selective inhibitor of c-kit

receptor tyrosine kinase, inhibited evoked smooth muscle

contraction and spontaneous activity in human OAB but not

in normal detrusor. Systemic administration of imatinib

mesylate improved bladder capacity, compliance, voided

volume, and urinary frequency, and it reduced contraction

thresholds and spontaneous activity during guinea pig

cystometry[35].

3.1.4. Detrusor and prostatic smooth muscle

Bladder hypertrophy is a consistent response following

obstruction in animal models and men[3638]. Alterations

in the smooth muscle structure, in the extracellular matrix,

and in the neuronal control and blood flow/ischemia have

been associated with the pathophysiology of LUTS [39].

Contractile proteins, such as desmin, actin, and myosin,

were shown to be altered in rats with partial urethral

obstruction (PUO) and in men with BOO [39]. An increase in

collagen deposition was observed in rats with PUO.

[

Fig. 1 Pathophysiologic mechanisms and targets for pharmacotherapy for male lower urinary tract symptoms. Ach = acetylcholine; ANS = autonomic

nervous system; ATP = adenosine triphosphate; CB-R = cannabinoid receptors; M3-R = M3 muscarinic receptor; NGF = nerve growth factor; NO = nitric

oxide; P-R = purinergic receptors; TRP = transient receptor potential (channels); a1a-AR = a1A-adrenoreceptor;a1D-AR = a1D-adrenoreceptor;b3-AR =

b3-adrenoreceptor.



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Increased levels of basic fibroblast growth factor, epidermal

growth factor (EGF), heparin-binding EGF-like growth

factor, insuline-like growth factor 1, NGF, and connective

tissue growth factor were demonstrated [39,40]. Growth

and phenotypic differentiation of sensory afferents and

sympathetic efferents in hypertrophied bladders has been

attributed to NGF, which may also influence spinal

micturition pathways, modulating voiding reflexes, andpain sensation in pathologic conditions[41]. Ischemia may

also play a role in bladder hypertrophy. BOO models are

associated with a decrease in bladder blood flow[42], and

prevention of ischemia decreases bladder hypertrophy and

improves detrusor contractility[43].

An abnormally upregulated ROK pathway may alter

muscle relaxation in the prostate, urethra, and bladder neck

in male LUTS. RhoA/ROK inhibits myosin light chain

phosphatase and increases the Ca2+ sensitivity of smooth

muscle contraction [44]. RhoA expression was intense in

prostatic smooth muscle cells of spontaneously hyperten-

sive rats[44]. In rats with PUO, bladder hypertrophy was

accompanied by higher expression of RhoA and ROK, lower

myosin phosphatase activity, and enhanced relaxant effects

of Y27632, a ROK inhibitor [45]. Pelvic ischemia and/or

atherosclerosis have also been associated with upregulation

of the ROK pathway[46].

3.1.5. Neurotransmitters, neuromodulators, receptors, and neural

pathways

3.1.5.1. Norepinephrine and adrenergic receptors. Prostatic stromal

cells express a1 receptors, more specifically a1A, which

provide the prostatic muscle tone. This concept led to the

development of a-blockers for the treatment of LUTS

associated with BPO. However, the mechanism of action of

these drugs has recently been questioned, given their small

effect on urodynamically proven BOO and the poor correla-

tion after treatment between the improvement of LUTS and

obstruction. There is discussion about the effect ofa-blockers

on extraprostatic a-ARs, such as those in the bladder and

spinal cord, andon other AR subtypes, especiallya1D-AR[47].

There is experimental evidence that BOO, although not

changing the relative expression ofa1-AR subtypes [48], may

enhance the response ofa1A-AR to adrenergic agonists[49].

Naftopidil, ana1D/a1A-AR selective antagonist (rather a1D-

AR selective), increased the volumeat first desire to void and

the volume at maximum desire to void while decreasing DO,

which might imply a roleatleast in partinsensoryafferent

nerve activity[50].

In the bladder, b-ARs predominate over a-ARs, and the

response of the normal detrusor to norepinephrine is

relaxation. In human bladder smooth muscle, b3-ARs are

the predominant subtype, both in concentration and in

physiologic importance. b3-AR agonists have relaxant

effects in vitro and in animal models of DO [51,52].

b3-ARs are also expressed in the rat sacral spinal cord.

PUO upregulates these adrenoceptors; intrathecal injection

of a b3-AR agonist improved bladder function in obstructed

animals with no effect on sham-operated animals, indicat-

ing that b3-AR containing central nervous pathways may be

relevant[53].

3.1.5.2. Acetylcholine and muscarinic receptors. The detrusor

muscle contains muscarinic receptors (MRs), mainly M2

and M3. M3 receptors are mainly responsible for normal

micturition contractions, which depend on Ca2+ mobiliza-

tion through the activation of the PLC-IP3 pathway, Ca2+

entry through nifedipine-sensitive channels, and activation

of the ROK pathway [27,51]. The antimuscarinics are

generally assumed to deliver their beneficial effects byblocking MRs on the detrusor muscle. However, increasing

evidence now indicates that additional effects involve M3

within the urothelium/suburothelium including bladder

afferent nerves [54]. Because antimuscarinics in clinical

doses have comparatively modest effects on voiding

contractions, their clinical efficacy may reflect influences

on the abnormal leak of ACh, from nerve endings or non-

neuronal sources during the storage phase that may cause

focal myogenic activity or urothelium-sensory fiber stimu-

lation[27].

3.1.5.3. Transient receptor potential channel superfamily. Members

of the transient receptor potential (TRP) family channelsmay respond to stretch and/or chemical irritation, and they

participate in urothelialafferent interactions that underlie

sensory perception and overall bladder function. Several

members of this receptor family have been implicated in

LUTS pathophysiology[55]. In a subgroup of patients with

idiopathic DO responding to intravesical resiniferatoxin

treatment, bladder TRPV1 messenger RNA (mRNA) expres-

sion was higher than in nonresponders and controls[56]. In

addition, patients with increased filling sensation exhibited

upregulation of TRPV1 mRNA in the trigonal mucosa, which

was inversely correlated with the bladder volume at first

sensation during filling cystometry [57]. Urothelial TRPV1

and TRPV4 activation increases ATP release, which may

contribute to DO and OAB pathophysiology[58].

3.1.5.4. Cannabinoids and cannabinoid receptors. The interest in

the modulatory effect of cannabinoid (CB) receptor agonists

on voiding function started with the report of improvement

of LUTS in patients with multiple sclerosis (MS) using

smoked cannabis [59]. CBs act on at least two types of

receptors: CB1 and CB2 expressed in several structures of

the bladder including urothelium and sensory fibers

[60,61]. Sensitization of bladder afferents by inflammation

can be partly suppressed by activation of CB receptors, an

effect that appears to be mediated by CB1[62]. Fatty acid

amide hydrolase (FAAH), the key enzyme for the degrada-

tion of the endogenous cannabinoid agonist anandamide, is

expressed in human, mouse, and rat bladder mucosa. FAAH

increases anandamide in the bladder tissues and activates

CB2 expressed in the urothelium and bladder afferents [63].

In addition to modulating afferent signaling, CB2 receptors

also seem to influence cholinergic nerve activity[60].

3.1.5.5. Adenosine triphosphate and purinergic receptors. Although

negligible in normal human detrusor neuromuscular

excitation, ATP participation in detrusor contraction is

prominent in other species and in pathologic conditions in

humans, particularly with DO. In vitro bladder preparations



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from patients with OAB and BOO showed a greater

contractile response to ATP compared with specimens from

normal bladders. In addition, ecto-adenosine triphospha-

tase activity was lower in overactive bladders, which may

lead to greater access to ATP and enhanced contractile

activity, contributing to DO [64]. In another study, P2X1 was

the main purinoceptor in male human bladder, and its

mRNA expression was higher in BOO [65]. In an in vitrostudy with porcine detrusor strips, detrusor motor drive

was enhanced by excitatory muscular P2X1 and by neural

P2X3 subunits, facilitating the release of ACh. The experi-

mentally induced downregulation of purine breakdown

produced smooth muscle hyperactivity that wasreduced by

the P2X1,3blockade[66].

3.1.5.6. Nitric oxide/cyclic guanosine monophosphate activity. NO

acts as a nonadrenergic, noncholinergic inhibitory factor

responsible for urethral relaxation during voiding and

possibly for bladder relaxation during the filling phase[51].

NO has an inhibitory effect on afferent nerve activity[17].

Expression of all the key enzymes of the NO/cyclicguanosine monophosphate (cGMP) signal has been dem-

onstrated in the human prostate. The PDE5 isoenzymes are

highly expressed in the bladder, prostate, and their

supporting vasculature [67]. In the bladder, NOS-containing

nerves are present. Furthermore, the NO/cGMP pathway

can modulate smooth muscle cell proliferation, through

protein kinase C inhibition[68].

3.1.6. Inflammation

The observation of chronic inflammation coexisting with

BPH histologic changes in pathologic specimens led to the

suspicionthat inflammationplays a role in thedevelopment

of prostate enlargement and LUTS/BPH[69]. In a retrospec-

tive analysis of 1700 BPH patients, chronic inflammation

and prostate volume were correlated [70]. Prostatic

inflammation was associated with overall clinical progres-

sion and increased incidence of acute urinary retention

(AUR) [71]. A positive association between high plasma

C-reactive protein levels and the odds of reporting

moderate to severe LUTS (American Urological Association

Symptom Index [AUA-SI] 8) was reported[72].

Local inflammation may be triggered by a viral or

bacterial infection, which would lead to the secretion of

cytokines, chemokines, and growth factors involved in the

inflammatory response with consequent growth of epithe-

lial and stromal prostatic cells. It has been hypothesized

that the inflammatory response is perpetuated by the

release of prostatic self-antigens following tissue damage,

which would sensitize the immune system and start

autoimmune responses. Important factors in this process

are the prostatic stromal cells, which activate CD4+

lymphocytes and proinflammatory cytokines and chemo-

kines, such as stromal-derived interleukin-8[73].

Prostanoids (prostaglandins [PGs] and thromboxanes)

are synthesized by cyclo-oxygenases (COX-1 and -2)

in the bladder after different physiologic stimuli, injuries,

and nerve stimulation, and by agents such as ATP and

mediators of inflammation. In rats, intravesical instillation

of prostaglandin E 2 (PGE2) was shownto cause DO [74,75].

BOO in rats was associated with a higher expression of

COX-2, suggesting that PGs may be involved in the

development of bladder hypertrophy and DO [76,77].

Higher levels of PGE2 and of PGE2 and prostaglandin F2a

(PGF2a) were found in the urine of men and women with

OAB, respectively [78,79]. PGs have been shown to

sensitize bladder afferent nerves via different prostanoidreceptors[32].

3.1.7. Metabolic factors

Body weight, body mass index (BMI), and waist circumfer-

ence have all been positively associated with prostate

volume in multiple study populations[80]. In the Baltimore

Longitudinal Study of Aging cohort, each 1 kg/m2 increase in

BMI corresponded to a 0.41-ml increase in prostate volume.

Obese (BMI35 kg/m2) participants had a 3.5-fold increased

risk of prostate enlargement compared with nonobese (BMI


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treatment because many urologists believe that male LUTS

are always secondary to the prostate. There is also the

common perception that these drugs may impair the

detrusor contraction and therefore be detrimental in a

presumed obstructed patient[11,87]. To address this issue,

several RCTs evaluated the effect of the combination of

antimuscarinics anda-blockers. The combination was more

effective at reducing male LUTS than a1-AR antagonists

alone in men with OAB and coexisting BPO. Moreover, the

combination was safe because the increase in postvoid

residual (PVR) and the incidence of AUR were, in general,

clinically negligible. It is important to note, however, that

most of the studies defined an upper limit of PVR of 200 ml

and a lower limit of Qmaxof 5 ml/s in their inclusion criteria

[8893].

3.2.3. The b3 adrenergic agonists

The b3 selective agonists, which include mirabegron and

solabegron, are currently being evaluated or used for the

treatment of OAB. Currently, clinical trials with solabegron

have only enrolled women, which has not been the case

with mirabegron[94]. In a phase 3 North American RCT,

1328 patients (25.7% men) were randomized to received

placebo or mirabegron 50 or 100 mg once daily for 12 mo.

In the European-Australian phase 3 trial, 1978 patients

(27.8% men) were randomized to receive placebo, mirabe-

gron 50 or 100 mg, or tolterodine sustained release (SR)

4 mg once daily for 12 wk. Both doses of mirabegron

showed significant improvement in incontinence, frequen-

cy, urgency, nocturia, and voided volume per micturition at

week 12. Improvements in incontinence and frequency

were evident at the first measured time point (4 wk). The

global incidence of AEs was similar across the four study

groups with the exception of dry mouth that was higher in

the tolterodine SR group [95]. Unfortunately, a post hoc

analysis of the two phase 3 trials with mirabegron to

analyze the effect of the compound exclusively in men is

not available. Nevertheless, the safety of mirabegron was

urodynamically evaluated in 200 men with LUTS and BOO.

Patients were randomized to receive mirabegron 50 mg,

mirabegron 100 mg, or placebo once daily for 12 wk.

Mirabegron at both doses had no effect on urinary flow,

detrusor pressure at maximum flow, or bladder contractil-

ity. PVR was marginally increased by mirabegron 100 mg

but not 50 mg[96].

3.2.4. Phosphodiesterase inhibitors

Based on the relaxant effects of drugs on smooth muscle

(prostate, urethra, detrusor) and on the association between

LUTS and erectile dysfunction, the use of PDE5 inhibitors

(PDE5-Is) has been investigated in the treatment of male

LUTS[97]. The precise mechanism(s) of action of PDE5-I on

LUTS, however, remains to be elucidated. As discussed by

Andersson et al, PDE5-Is may act on several pathways

including upregulating NO/cGMP activity, downregulating

Rho-kinase activity, modulating autonomic nervous system

overactivity and bladder and prostate afferent nerves,

increasing pelvic blood perfusion, and reducing inflamma-

tion[17].Several clinical trials on the effect of PDE5-Is on

male LUTS have been published. In these studies, different

PDE5-Is (sildenafil, vardenafil, tadalafil, and UK-369003) and

combinations of ana-blocker (alfuzosin or tamsulosin) and

PDE5-I were compared with placebo or to a-blocker alone.

According to a recent meta-analysis, the use of PDE5-I alone

was associated with a significant improvement of IPSS at

the end of the studies compared with placebo [98].

The association of an a-blocker and PDE5-I significantly

improved IPSS and Qmaxat the end of the studies compared

with a-blockers alone [97,98]. Tadalafil is now approved

by the US Food and Drug Administration for male LUTS

management.

Table 1 Future pharmacotherapy for non-neurogenic male lower urinary tract symptoms, their respective targets, and phase of studies

Class of drugs Target Phase of studies References

Antimuscarinics M3 muscarinic receptors Clinical practice [8893]

Phosphodiesterase inhibitors NO/cGMP Clinical practice [97,98]

ROK

Autonomic nervous system

Afferent nerves

Blood perfusionInflammation

b3-agonists b3-adrenergic receptor Phase 2 (completed) [9496]

Clinical practice

Botulinum toxin Acetylcholine release Clinical practice [125,127]

Prostate tissue Phase 3 (currently)

LHRH antagonists Testosterone Phase 3 (completed) [84,85]

Cannabinoids Cannabinoid receptors Phase 3 (completed) [115,116]

NX-1207 Prostate tissue Phase 3 (currently) [122]

PRX-302 Prostate tissue Phase 2 (completed) [124]

Vitamin D3 receptor analogs Vitamin D3 receptors Phase 2 (completed) [110]

Anti-inflammatory drugs Inflammation Phase 1 [100,101]

Transient receptor potential channel blockers Transient receptor potential channels Experimental [111113]

Rho-kinase inhibitors ROK Experimental [117119]

Purinergic receptor blockers Purinergic receptors Experimental [120]

Endothelin-converting enzyme inhibitors Detrusor muscle Experimental [121]

cGMP = cyclic guanosine triphosphate; LHRH = luteinizing hormone-releasing hormone; NO = nitric oxide; ROK = RhoA/Rho kinase.



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3.2.5. Anti-inflammatory drugs

In an experimental model of BPH in rats treated with

flavocoxid, a dual inhibitor of COX-2 and 5-lipoxygenase

(5-LOX), reduced prostate weight and hyperplasia was

observed, and inducible expression of COX-2 and 5-LOX

and the production of PGE2 and leukotriene B4 wereblunted.

The drug also enhanced apoptosis pathways and decreased

GF expression [99]. The combination of rofecoxib andfinasteride caused a significantly higher improvement in

IPSS and Qmax thanfinasteride alone at 4 wk but not at 24 wk

[100]. The combination of tenoxicam and doxazosin had a

superior effecton theIPSS, IPSS-quality of life (QoL), andOAB

SymptomScore thandoxazosinaloneat 6 wk, in particular on

storagesymptoms[101]. However, no large RCTsfollowed,so

the results should be interpreted with caution.

3.2.6. Vitamin D3 receptor analogs

Human prostatic urethra, prostate, and bladder exhibit

vitamin D3 receptors (VDRs) [102]. Elocalcitol, a VDR

agonist, may decrease stromal prostate cell proliferation,

even in the presence of GFs, and induce apoptosis withoutinterfering with AR signaling [103]. In human and rat

bladder smooth muscle, elocalcitol also inhibited RhoA/ROK

signaling[104]and limited the COX2/PGE2 pathway [105].

In a rat model of BOO, dailytreatment with elocalcitol for

14 d, in a nonhypercalcemic dose, did not prevent bladder

hypertrophy, but it reduced the occurrence of spontaneous

contractions and the decrease in contractility of the

detrusor that occurred with increasing bladder weight,

both in vivo and in vitro [106]. Previous treatment with

elocalcitol enhanced the effects of tolterodine on bladder

compliance of rats with partial BOO[107].

A phase 2 RCT could not demonstrate differences in Qmaxand symptoms between elocalcitol and placebo, however,

despite the capacity to arrest prostate growthin men50yr

of age with prostatic volume 40 ml [108,109]. A recent

phase 2b RCT caused a revival of interest in elocalcitol after

showing a significant reduction in incontinence episodes

and improvement of the Patients Perception of Bladder

Condition in women with OAB. Unfortunately, male

patients were not included[110].

3.2.7. Transient receptor potential channel blockers

Experimental data on the effect of drugs interacting with

TRP channels in regard to LUTS have been published;

however, no proof-of-concept studies in humans are avail-

able. Most of the data on TRP channel blockers originate from

inflammation models. In animal models of cystitis or spinal

cord transection GRC 6211, an orally active TRPV1 antagonist

counteracted bladder hyperactivity and noxious input. At the

same doses, the compound had no effect on bladder function

in sham animals [111]. Likewise, the TRPV4 antagonist

HC-067047 also dose-dependently decreased the voiding

frequency and increased the voided volume. However, at the

same doses the TRPV4 antagonist also affected sham animals

[112]. Systemic coadministration of TRPV1 and TRPV4

antagonists showed an interesting synergistic effect in DO

[113]. No studies are available in humans due to the

hyperthermic effect of these drugs in pilot studies.

3.2.8. Cannabinoids

Clinical studies with the use of cannabinoids on LUTS are

scarce and essentially restricted to MS patients. The efficacy

of whole plant extracts ofCannabis sativa was demonstrated

in MS patients with LUTS, who experienced significant

improvement in urgency, incontinence, frequency, and

nocturia[114]. In the multicenter trial of the Cannabinoids

in Multiple Sclerosis study, patients who used cannabisextract or D9-tetrahydrocannabinol achieved a significant

reduction in incontinence episodes over matched placebos

[115]. In contrast, Sativex (nabiximols), an endocannabi-

noid system modulator, failed to reach statistical signifi-

cance in the primary end point, reduction in the daily

number of incontinence episodes. The number of daytime

voids, total voids per day, and nocturia, however, were

significantly reduced in the Sativex group[116].

3.2.9. Rho-kinase inhibitors

Treatment with hydroxyfasudil, a nonselective Rho-kinase

inhibitor, ameliorated the bladder dysfunction in male

spontaneous hypertensive rats (SHRs). Micturition frequen-cy, single voided volume, and intercontraction interval

improved in hydroxyfasudil-treated animals compared

with nontreated ones. Bladder blood flow and NGF content

in the bladders of the treated animals were similar to those

of healthy control animals. The authors theorized that

bladder ischemia may be responsible for NGF overexpres-

sion in the bladder of SHRs and that hydroxyfasudil

ameliorates bladder dysfunction by improving bladder

blood flow and ischemia-induced bladder damage [117].

In another experimental study with cyclophosphamide-

induced cystitis in rats, hydroxyfasudil significantly in-

creased voided volume and decreased maximum detrusor

pressure, whereas the intercontraction interval was not

significantly affected. In vitro, the maximum contraction of

the concentration-response curves to carbachol was signif-

icantly lower in the hydroxyfasudil group[118]. Likewise,

another Rho-kinase inhibitor, Y-27632, attenuated the

phasic and sustained contraction induced by carbachol in

both control and obstructed bladders from rats. The

inhibitory effect of Y-27632 was enhanced on the sustained

responses to carbachol in the obstructed bladders [119].

3.2.10. Purinergic receptor blockers

In an experimental model of neurogenic bladder induced by

spinal cord injury (SCI) in female rats, the P2X3/P2X2/3

antagonist AF-353 reduced the field potential in the dorsal

horn in response to sudden increase in intravesical pressure.

In addition, during cystometry the frequency of nonvoiding

contractions was significantly reduced in SCI animals[120].

3.2.11. Endothelin-converting enzyme inhibitors

Endothelin (ET)-1 is a potent vasoconstrictor that has been

shown to contract human detrusor and is overexpressed in

the detrusor muscle in a rabbit BOO model. Endothelin-

converting enzyme (ECE) is responsible for the generation

of ET-1. It was hypothesized that the inhibition of ECE

could prevent some bladder changes following BOO; thus

WO-03028719, an oral ECE inhibitor, was given to



8/12

obstructed female rats, leading to a reduction in the

incidence of nonvoiding contractions and in the amplitude

of normal voiding contractions. The drug has not been

tested in humans[121].

3.2.12. Drugs injected into the prostate

3.2.12.1. NX-1207. NX-1207 is an investigational drug for the

treatment of LUTS/BPH, currently in phase 3 clinical trials. Itis a new therapeutic protein of proprietary composition

with selective proapoptotic properties. The drug is injected

under transrectal ultrasound guidance into the transition

zone of the prostate. The drug produces focal cell loss

through apoptosis, leading to prostate tissue shrinkage. In

the first US phase 2 clinical trial, three doses of NX-1207

(2.5, 5.0, and 10 mg) were evaluated in a multicenter RCT

involving 175 men. The dose of 2.5 mg was selected as the

smallest dose showing clinically significant efficacy (mean

improvement in AUA-SI: 11.0). The second trial, a multi-

center randomized noninferiority study, evaluated two

doses (2.5 and 0.125 mg) and an active open-label

comparator (finasteride). The mean AUA-SI improvementafter 90 d in the intent-to-treat group was 9.71 points for

2.5 mg NX-1207 versus 4.13 points for finasteride

(p= 0.001) and 4.29 for 0.125 mg NX-1207 (p= 0.034).

The 180-d results also were positive (NX-1207 2.5 mg

noninferior to open-label finasteride). None of the clinical

studies identified safety issues relating to NX-1207 itself or

sexual side effects. The drug is currently under investigation

in phase 3 clinical trials in the United States [122].

3.2.12.2. PRX302. PRX302 is a prostate-specific antigen (PSA)-

activated protoxin produced via a modified proaerolysin,

the inactive precursor of a bacterial cytolytic pore-forming

protein. Interestingly, the protoxin requires proteolytic

processing by PSA for activation. When injected into the

nonPSA-producing dog prostate, PRX302 was inactive,

whereas its ability to ablate prostate tissue was observed in

the PSA-producing monkey prostate[123].

PRX302 was injected transperineally under transrectal

ultrasound guidance into the right and left transition zone

in a study of 33 patients with BPH [124]. Inphase 1 (n= 15),

subjects received increasing concentrations of PRX302 at a

fixed volume. In phase 2 (n= 18), the concentration was

fixed and the volumes varied. In both phases, a decrease in

total IPSS was observed in all cohorts. In phase 1, no

relationship between IPSS response and dose was observed.

In the phase 1 and 2 studies, respectively, a decrease 30%

in IPSS was observed in 73% and 67% at day 90, and 64% and

67% in 1 yr. Patients also experienced improvement in QoL

and reduction in prostate volume out to day 360. A

statistically significant decrease in mean Qmax was observed

at day 90 in the phase 1 study, which was not sustained out

to 1 yr. In the phase 2 study, a 2.8 ml/s improvement was

noted out to 1 yr. PRX302 injection decreased prostate

mass, with most patients showing a 20% reduction in

prostate volume after 1 yr. The injection>1 ml had the best

overall results. Erectile function was not altered by the

treatment. AEs were mild to moderate and transient in

nature. The small sample of the studies, however, is a major

limitation, particularly because repeated dosing of the toxin

may lead to an antibody response [124]. Nonetheless, the

preliminary safety and efficacy data make PRX302 a

promising minimally invasive targeted treatment for LUTS

associated with BPH.

3.2.12.3. Botulinum toxin. Botulinum neurotoxin (BoNT) pre-

vents exocytosis of ACh vesicles at the nerve terminal,thereby inhibiting neurotransmission and muscle contrac-

tion. The action of BoNT is not permanent because neuronal

death does not occur, and eventually the toxin is inactivated

and removed. BoNT subtype A (BoNTA) is the most relevant

clinically. OnabotulinumtoxinA (BoNT-ONA), abobotuli-

numtoxinA, and incobotulinumtoxinA are available BoNTAs

[125,126]. Recently, the use of BoNT-ONA in LUTS was

comprehensively reviewed. Its efficacy in the treatment of

idiopathic DO was demonstrated in several studies includ-

ing one RCT and a dose-ranging trial. It seems that the dose

of 100 U may be the one that appropriately balances the

symptoms benefits with the safety profile[125]. Improve-

ment of LUTS associated with BPE has been reported withthe use of intraprostatic injection of BoNT-ONA in clinical

studies; however, the lack of placebo arms was always a

drawback. Recently, intraprostatic injection of BoNT-ONA

100 U, 200 U, and 300 U was tested versus placebo injection

in a phase 2 dose-ranging study. IPSS, Qmax, and prostate

volume significantly improved in all groups, owing to

a large placebo effect from the injectable therapy. A

post hoc analysis revealed a significant reduction with

BoNT-ONA 100 U in prior a-blocker users at week 12, which

will be explored in further studies[127].

4. Conclusions

The pathophysiology of male LUTS is highly complex and

multifactorial. Changes in the bladder and prostate as well

as in related structures, such as the pelvic vasculature and

innervation, account for alterations in the normal physiol-

ogy of the male lower urinary tract. Derangements at the

structural, molecular, and cellular levels have been identi-

fied, and new pathophysiologic mechanisms are continually

described. Different categories of symptoms usually over-

lap, making it difficult to pinpoint one guilty organ, leading

to a broader and more symptom-driven approach to the

condition. In this scenario, new drugs have been suggested

either as standalone or as add-on treatments to currently

established treatments for male LUTS. Some of these drugs

are currently being used in clinical practice with short-term

results; others are still in clinical or experimental evalua-

tion. Even though some of the new treatments may be

promising alternatives, there is still a long way to go until

patients can benefit from them.

Author contributions: Francisco Cruz had full access to all the data in the

study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Soler, Gratzke, Cruz.

Acquisition of data: Soler, Cruz.

Analysis and interpretation of data: Soler, Cruz, Chapple, Andersson.



9/12

Drafting of the manuscript: Soler, Cruz.

Critical revision of the manuscript for important intellectual content:

Chapple, Andersson, Drake, Gratzke, de Groat, Chancellor, Lee.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: Soler

Supervision: Cruz.

Other(specify): None.

Financial disclosures: FranciscoCruz certifies that allconflictsof interest,

including specific financial interests and relationships and affiliations

relevant to the subject matter or materials discussed in the manuscript

(eg, employment/affiliation, grants or funding, consultancies, honoraria,

stock ownership or options, expert testimony, royalties, or patents filed,

received, or pending), are the following: Roberto Soler is a consultant for

Astellas. Karl-Erik Andersson is a consultant for Astellas, Allergan, Pfizer,

Ferring, and TheraVida. Michael Chancellor is a consultant for Allergan,

Astellas, Cook, Lipella, Merck, Pfizer, and Targacept. He is an investigator

for Allergan, Cook, Lipella, and Medtronic. Christopher Chapple is a

speaker for Ranbaxy; a consultant for AMS and Lilly; a consultant and

researcher for ONO; and a consultant, researcher, and speaker for

Allergan, Astellas, Pfizer, and Recordati. William de Groat is a consultant

for Medtronic, Ethicon, Eli Lilly, Amphora Medical, Endo Pharmaceutical,

and Circuit Therapeutics; he receives speaker honoraria for Medtronic

andAstellasand research grantsfrom Astellas andEli Lilly.MarcusDrake

is a consultant, researcher, and speaker for Allergan, Atellas, Ferring, and

Pfizer. Christian Gratzke is a consultant, researcher, or speaker for

Astellas, Recordati, Rottapharm Madaus, Lilly, AMS, Bayer Healthcare,

and GSK. Richard Lee has nothing to disclose. Francisco Cruz is a

consultant for Allergan, Astellas, Recordati, and Janssen, and an

investigator or speaker for Allergan, Astellas, and Janssen.

Funding/Support and role of the sponsor: None.

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Documents

Future Direction in Pharmacotherapy for Non-Neurogenic Male Lower Urinary Tract Symptoms